The present invention relates to therapeutic agents for lymphatic tumors (excluding myeloma) comprising as an active ingredient antibodies that specifically bind to proteins expressed in said lymphatic tumors. The present invention also relates to therapeutic agents for T cell tumors or B cell tumors (excluding myeloma). Furthermore, the present invention relates to antibodies that specifically bind to proteins expressed in lymphatic tumors and that have a cytotoxic activity.
Lymphatic cells are mainly responsible for immunity in the living body. Lymphatic cells are all derived from the same hemopoietic stem cells, which are released into the peripheral blood after repeated differentiation by the action of various differentiation inducing factors or growth factors in the bone marrow or other organs. Due to differences in such differentiation, lymphocytes are broadly classified into the B cells and the T cells. The B cells are thought to have the ability of producing antibodies whereas the T cells are thought to have the ability of antigen presentation, cytotoxicity and the like. When these cells undergo tumorigenic change for some reason or other during certain stages of differentiation and begin to proliferate in an uncontrolled manner in the bone marrow, the lymphatic tissues, the blood or the like, such a state is called a lymphatic tumor.
Because of the introduction of new technologies, in particular technological advances that make use of monoclonal antibodies against differentiation antigens on the cell surface, it has become possible to identify the origin and/or the differentiation stage of lymphatic cells. Accompanied by this, it has also become possible not only to determine whether such tumor cells are derived from T cells or B cells but also to identify the degree of maturity of tumor cells.
Lymphatic tumors are broadly classified into the B cell tumors and the T cell tumors based on the origin and degree of maturity of tumor cells. Based on the degree of maturity of tumor cells, the B cell tumors are classified into acute B lymphatic leukemia (B-ALL), chronic B lymphatic leukemia (B-CLL), pre-B lymphoma, Burkitt lymphoma, follicular lymphoma, follicular pallium lymphoma, diffuse lymphoma and the like. On the other hand, the T cell tumors are classified, based on the degree of maturity of tumor cells, into acute T lymphatic leukemia (T-ALL), chronic T lymphatic leukemia (T-CLL), adult T cell leukemia (ATL), non-ATL peripheral T lymphoma (PNTL) and the like (Zukai Rinsho [Gan] (Illustrated Clinical: Cancer), series No. 17 Leukemia and lymphoma, Takashi Sugimura et al., Medical View Co., Ltd., 1987, B cell tumors, Kiyoshi Takatsuki, Nishimura Shoten, 1991).
It is true that, despite recent advances in the medical technologies, treatments of lymphatic tumors are not satisfactory. The cure rate of acute lymphatic leukemia (ALL), for example, is still 20% or lower, and that of lymphoma is still about 50% at the advanced stage although the cure rate for B lymphoma is said to be relatively high due to the progress of multi-drug therapies. Furthermore, T lymphoma is more intractable and has a cure rate of about 30%, and the rate is under 10% for adult T cell leukemia (ATL) at present.
On the other hand, Goto, T. et al. have reported a monoclonal antibody (anti-HM1.24 antibody) that was obtained by immunizing mice with human myeloma cells (Blood (1994) 84, 1922-1930). When anti-HM1.24 antibody was administered to a mouse transplanted with human myeloma cells, the antibody accumulated in tumor tissues in a specific manner (Masaaki Kosaka et al., Nippon Rinsho (Japan Clinical) (1995) 53, 627-635), suggesting that anti-HM1.24 antibody could be applied in the diagnosis of tumor localization by radioisotopic labeling, missile therapies such as radioimmunotherapy, and the like. However, it is not known that anti-HM1.24 antibody is useful for treatment of other lymphatic tumors.
Therapeutic methods for lymphatic tumors that are currently used include various chemotherapies, X-ray therapies, bone marrow transplantation and the like. As mentioned above, however, none of these are yet satisfactory for the diseases, and thus epoch-making therapeutic agents or methods that can alleviate lymphatic tumors and prolong the survival period of the patient are being awaited.
Thus, it is an object of the present invention to provide a new therapeutic agent for lymphatic tumors excluding myeloma.
In order to provide such a therapeutic agent, the inventors have extensively conducted in vitro studies including flow cytometry (FCM) analysis, determination of cytotoxic activities such as an ADCC activity, a CDC activity, etc. and in vivo studies on antitumor effects using anti-HM1.24 antibody (Goto, T. et al., Blood (1994) 84, 1922-1930), and studies on the isolation of the antigen protein to which anti-HM1.24 antibody specifically binds. As a result, the inventors have found that the antigen protein recognized by anti-HM1.24 antibody is being expressed on lymphatic tumors and that anti-HM1.24 antibody has an antitumor effect on lymphatic tumors, and thereby have completed the present invention.
Thus, the present invention provides a therapeutic agent for lymphatic tumors (excluding myeloma) comprising as an active ingredient an antibody that specifically binds to a protein having the amino acid sequence as set forth in SEQ ID NO:1 and SEQ ID NO:5 and that has a cytotoxic activity.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising as an active ingredient an antibody that specifically binds to a protein having the amino acid sequence as set forth in SEQ ID NO:1 and SEQ ID NO:5 and that has a cytotoxic activity.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising as an active ingredient a monoclonal antibody that specifically binds to a protein having the amino acid sequence as set forth in SEQ ID NO:1 and SEQ ID NO:5 and that has a cytotoxic activity.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising as an active ingredient an antibody that specifically binds to a protein having the amino acid sequence as set forth in SEQ ID NO:1 and that has an ADCC activity or a CDC activity as the cytotoxic activity.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising as an active ingredient an antibody that specifically binds to a protein having the amino acid sequence as set forth in SEQ ID NO:1 and SEQ ID NO:5, that has a cytotoxic activity, and that has Cxcex3 of human antibody as the constant region.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising as an active ingredient a chimeric antibody or a humanized antibody that specifically binds to a protein having the amino acid sequence as set forth in SEQ ID NO:1 and SEQ ID NO:5 and that has a cytotoxic activity.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising as an active ingredient an antibody that specifically binds to an epitope recognized by anti-HM1.24 antibody.
The present invention also provides a therapeutic agent for T cell tumors or a therapeutic agent for B cell tumors (excluding myeloma) comprising anti-HM1.24 antibody as an active ingredient.
Furthermore, the present invention relates to an antibody that specifically binds to a protein expressed on lymphatic tumors and that has a cytotoxic activity.